The field of the invention lies in ultrasound methods and apparatus for reducing tissue damage from ischemia by means of insonation. The invention pertains to therapeutic medical systems and, more particularly, to the therapeutic use of ultrasound methods and apparatus for reducing tissue damage from ischemia.
The insonation of the instant invention has the goals of reducing edema and promoting microcirculation, recanalization, collateral and interstitial flow, and delivery of lytic agents to clots located in supplying arteries, as well as delivery of nutrients and/or drugs to the ischemic tissue. Goals of the apparatus and method may even extend to clot destruction through a re-enforced focusing of multiple beams.
More particularly, in accordance with the methods and apparatus of the instant invention, at least a portion if not all of an organ affected by ischemia is exposed to low frequency low power ultrasound, preferably generated by a plurality of transducers from directions spanning at least a 45xc2x0 angle and over at least a one minute period, preferably over an hour period, more preferably over many hours. The system can also be used to maintain and enhance biological tissue function and viability in a setting of reduced perfusion by exposure to ultrasound energy transmission.
The principles taught, demonstrated and tested herein use the reduction of tissue damage from brain ischemia as a preferred embodiment, brain ischemia offering a most difficult test case. The bone attenuation of ultrasound has not received extensive consideration in the art. The effect of the cranium bone structure, in particular, has presented itself as a significant obstacle to insonation of the brain.
Addressing brain ischemia in general, a significant reduction in cerebral blood flow leads to brain ischemia and, if untreated, may cause stroke leading to permanent tissue damage (infarction), severe disability, and, in many cases, death. In particular, an ischemic stroke occurs when a thrombus obstructs cerebral arteries. Systemically-induced thrombolysis with intravenous tissue plasminogen activator (TPA) (see The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl J Med. 1995;333:1581-1587) is the only effective therapy practiced today to reduce damage from ischemic stroke.
Although intravenous tPA improves the outcome of stroke patients (see The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587) recanalization is not achieved in a significant portion of arterial occlusions (74% of cerebral arteries) when tPA is given alone (see del Zoppo G J, Poeck K, Pessin M S, Wolpert S M, Furlan A J. Ferbert A, Alberts M J, Zivin J A, Wechsler L, Busse O, Greenlee R, Brass L, Mohr J P, Feldmann E, Hacke W. Kase C S, Biller J, Gress D, Otis S M. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992; 32:78-86).
Ultrasound in the low MHz-kHz frequency range (see Akiyama M, Ishibashi T. Yamada T. Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Abstract of Neurosurgery 1998; 43:828-832 and Behrens S, Daffertshofer M, Spiegel D, Hennerici M. Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Abstract of Ultrasound Med Biol 1999; 25:269-273) has been shown to promote thrombolysis in vitro models of cerebral arterial thrombosis by substantially increasing the thrombolytic effect of tPA.
In other experiments, ultrasound exposure has been shown to cause various changes such as reversible disaggregation of uncrosslinked fibrin fibers (see Abstract of Braaten J V, Goss R A, Francis C W. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost 1997;78:1063-1068), microcavity formation in the shallow layer of thrombus (see Abstract of Kondo I, Mizushige K, Ueda T. Masugata H, Ohmori K, Matsuo H. Histological observations and the process of ultrasound contrast agent enhancement of tissue plasminogen activator thrombolysis with ultrasound exposure. Jpn Circ J 1999;63:478-484), and increasing the enzymatic transport of tPA improving uptake and penetration of tPA into clots (see Abstract of Francis C W, Onundarson P T, Carstensen E L, Blinc A, Meltzer R S, Schwarz K, Marder V J. Enhancement of fibrinolysis in vitro by ultrasound. J Clin Invest 1992; 90:2063-2068).
It has been concluded that ultrasound promotion of drug-induced lysis does not appear to be mediated by thermal or cavitational effects (see Abstract of Suchkova V, Siddiqi F N, Carstensen E L, Dalecki D, Child S, Francis C W. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998;98:1030-1035).
A 2 MHz pulsed wave ultrasound is used in the diagnostic equipment for cerebrovascular studies (see Otis S M, Ringelstein E B. The transcranial Doppler examination: principles and applications of transcranial Doppler sonography. In: Tegeler C H, Babikian V L, Gomez C R. Neurosonology. St Louis:Mosby, 1996. Pp 113-129). Some have suggested that the ideal frequency for ultrasound mediated thrombolysis appears to be the 1-2.2 MHz range (see Abstract of Blinc A, Francis C W, Trudnowski J L, Carstensen E L. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood 993;81:2636-2643). However, this level of insonation may not deliver sufficient energy to disrupt a brain clot mechanically, due to the tremendous attenuation of ultrasound through the skull bone (see Abstract of Akiyama M, Ishibashi T. Yamada T. Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Cite above Neurosurgery 1998; 43:828-832 and Behrens S, Daffertshofer M, Spiegel D, Hennerici M Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol 1999;25:269-273).
The impact of continuous exposure to ultrasound on cerebral ischemic tissue and on cerebral clots in human patients, in vivo, has not been studied before. Its utility, thus, has not previously been raised to the level reached by the instant demonstration. The instant invention is based upon both human and experimental animal model studies involving cerebral ischemic tissue. Methods and techniques suggested and indicated by the undertakings of the instant studies, however, are also applicable, as will be readily appreciated, to other tissue and organs.
Eggleton and Fry (see Eggleton R C, Fry F J. U.S. Pat. No. 3,951,140. Apr. 20, 1976) teach that low intensity ultrasound can be used to potentiate healing of various biological tissues, in particular the heart, by means of combating tissue swelling, increasing permeability of biological membranes, and inducing interstitial flow of fluids under radiation pressure (microstreaming). Although their patent discloses apparatus and method for therapeutic ultrasound insonation of ischemic tissue and energy transmission to infarcted tissue (in particular, the heart), their approach does not extend to teaching the identification of normal donor tissue for promoting collateral and/or interstitial flow, or to teaching methods and apparatus for utilizing beams that span at least 45xc2x0, or to utilizing beams that expose an entire organ or tissue to ultrasound.
No specific methods or ultrasound devices are taught by the prior art to particularly penetrate bones or to utilize vasculature in order to sonicate tissue at risk, as well as to sonicate normal tissue of the organ, all designed to limit tissue damage from ischemia. Jolez and Hynynen (see Jolesz F A, Hynynen K U.S. Pat. No. 5,752,515. May 19, 1998) disclose noninvasive methods and apparatus for delivery of various compounds through a blood brain barrier using ultrasound-induced cavitation and heating in a small target area (1 mm3-1 cm3). However, such hyperthermia exacerbates ischemic brain damage, and such cavitation is an adverse biological effect of ultrasound which should be avoided whenever possible unless focal tissue destruction is taught.
In sum, previously published papers and patents do not disclose the specific methods and apparatus taught herein for marshaling the impact of low frequency low power ultrasound exposure on ischemic tissues, vascular structure and/or normal donor tissue to mitigate permanent tissue damage. It is an object of this invention to provide detailed methods and apparatus for reducing biological tissue damage from ischemia by means of continuous insonation through intact skin and around and/or through bone which should result in the reduction of edema, promotion of microcirculation, interstitial fluid flow, recanalization, collateral flow and the delivery of lytic agents to clots located in supplying arteries as well as the delivery of nutrients, therapeutic substances and/or drugs to ischemic tissues. Even clot disruption is a possible modality. These and other objects are attained by the invention which provides methods and ultrasound apparatus for reducing biological tissue damage from ischemia and ischemia induced complications.
The methods and apparatus of the instant invention are demonstrated using brain ischemia as a prime, and a most difficult, example. The methods according to one aspect of the invention include applying ultrasound waves generated by multiple transducers to various portions of skin surface (areas extending in some cases to total areas exceeding an entire organ surface, as for instance to 90% of a skull surface) in order to expose supplying and draining vasculature, ischemic tissue and potential donor tissue, as a source of collateral flow and nutrients, (including potentially the entire organ) to low-power ( less than 1000 mW) low-frequency ultrasound. In the setting of brain ischemia, one experimental model as well as human studies indicate that ultrasound penetration through the skull can be sufficient to expose target tissue to acoustic pressure gradients and to detect residual flow around a clot in intracranial arteries. Studies indicate that ultrasound frequencies from 1 KHz to 10 MHz might be beneficially used, with the duration of sonication varying from 1 minute to 24 hours and with burst mode repetition varying from 0.1 Hz to continuous and with power varying from 1 mW to 1000 mW.
In one aspect of the invention, microstreaming is induced in the tissues which, utilizing the method and apparatus taught herein, may be harnessed to reduce tissue edema, deliver energy to ischemic cells, promote collateral and interstitial flow and promote drug/nutrients delivery to ischemic tissues. In a further aspect, the invention provides methods and apparatus that combine targeting and fluid, nutrient and drug delivery systems to the ischemic tissue areas with mechanical agitation of other targeted tissues, including clots, located in the vasculature. Viewed from another further aspect, the invention provides methods of maintaining biological tissue viability in a setting of reduced perfusion by exposing the entire ischemic tissue or organ to multi-directional ultrasound energy transmission. The invention further provides methods and apparatus that expose an ischemic organ to a plurality of ultrasonic waves, simultaneously and/or sequentially, with different frequencies, powers, pulse configurations and synchronization, to achieve enhancement of thrombolysis, edema reduction, energy delivery, promotion of collateral and interstitial flow, recanalization and an increase of venous outflow.
The invention includes a source of acoustic waves and apparatus for attachment to the source of acoustic waves. The apparatus comprises a plurality of transducer probes and a frame. The frame is structured such that the probes can be arranged to at least partially, and possibly completely, surround a human organ, targeted at selected tissues, and be held there in place. At least two acoustic beams produced by transmitting probes should be focusable to span at least a 45xc2x0 angle. Speaking more precisely, in order to reduce what is in reality three dimensions into two dimensional language, for ease of understanding, since two beams may not precisely lie in a single plane, in order to measure a 45xc2x0 angle it should be understood that the beams may need to be projected to a common plane. The closest common plane would be selected.
Preferably an acoustic beam source will include means for firing acoustic beams through its probes sequentially. The source also preferably includes means for emitting at least two beams of relatively narrow width, focusable to approximately intersect. The source apparatus preferably includes means for synchronizing emissions from two or more focused relatively narrow beams to effect, for instance, a beam reinforcement in at least a portion of an area of an intersection.
Preferably an acoustic source apparatus includes means for varying the power of a plurality of beams, as from 1 mW to 1000 mW, for varying the frequency of a plurality of beams, as from 1 KHz to 10 MHz, and for varying the pulse rate of a plurality of beams, as from 10 per second to continuous. Preferably the apparatus will include means for receiving reflected waves for diagnostic purposes with at least one probe, and possibly more.
The invention includes a method for the therapeutic use of ultrasound to enhance perfusion of tissue. The method includes identifying, in at least one organ tissue zone, a boundary between at least one normal tissue zone and one ischemic tissue zone. The method includes arranging a plurality of probes to direct acoustic beams, focused to span an angle of at least 45xc2x0, into the organ tissue zone, with at least one beam or beam set passing through the boundary to induce fluid motion across the boundary. The method includes applying insonation through the probes to the tissue zone for at least 1 minute, including preferably several hours, and up to 24 hours or more, and acoustic transmission monitoring, at least periodically, for indicia of perfusion for at least a portion of the tissue zone.
The method may include testing indicia of probe effectiveness and selecting probes to be activated based upon the testing. The testing may also indicate the selection of direction or focusing for beam propagation. Probes may be mechanically and/or electronically aligned and activated with mechanical or electronic steering. Test pulses emitted at different frequency ranges may permit estimating penetration through bone by an indicia of the strength of return echoes. The method may also include selecting position and direction for at least one beam based upon vasculature structure and/or bone structure around at least one zone. The method may also include firing acoustic beams sequentially and/or emitting at least two beams of relatively narrow focus and steering the beams to intersect. The method may include synchronizing emissions from at least two beams to effect a positive beam reinforcement in at least a portion of an area of intersection. Preferably the method includes producing a plurality of beams with independently variable power levels, independently variable frequency and independently variable pulse rate.